Title: Interventions that retard mammalian aging Aging-associated debilitation is a primary source of human misery. Healthy life spans in mammalian models can be increased by dietary and genetic means; however, no effective intervention applicable to humans has yet been validated in mammals. Human trials for "anti-aging" treatments are unlikely to proceed without such validation--the purpose of this RFA. The following aims are designed to definitively identify effective anti-aging interventions and to rule out those that are ineffective. Aim 1: To verify that potential anti-aging interventions produce their expected biological effects. For anti- inflammatory agents (corticosterone, ibuprofin, celecoxib), insulin sensitizing agents (CL316,243, rosiglitazone), agents that promote mitochondrial function or suppress oxidative damage (R-or lipoic acid, L- carnitine), and for multi-functional phytochemicals, the following will be determined: doses and modes of administration that produce biological effects, both short and long term, without toxicity or a decrease in food consumption. Aim 2: To test the hypotheses that potential anti-aging interventions in these three categories actually retard aging in biological systems and increase life spans. Noninvasive, longitudinal measures are made of growth, immune cells, insulin/glucose, collagen, healing and urine. Because aging is multifactorial, combinations of interventions proven in Aim 1 also will be tested. Aim 3: To confirm and augment the conclusions regarding interventions successful in the first phase of the program. Whether interventions that increase maximum life span also retard expression of aging in the following biological systems will be tested: Neurobehavorial/sensory, mitochondrial, gene expression and protein modification, followed by detailed histopathological analyses. Results in these systems may suggest mechanisms by which the interventions retard aging.